It is known that the suppression of the functions of bone marrow by various causes seriously worsens systemic condition to become dangerous to life. As morbidities due to such myelosuppressive conditions, hypoplastic anemia, thrombopenia, leukopenia and the like are known.
As the mechanism of the onset of leukopenia among them, the decrease of leukocyte production and the acceleration of leukocyte destruction are mentioned. Causes for the decrease of leukocyte production include congenital diseases, irradiation with radiation, hypoplastic anemia, administration of an antitumor agent or antibiotic, etc. On the other hand, causes for the acceleration of leukocyte destruction include infectious diseases, immunological abnormalities, etc.
As a therapeutic agent for leukopenia, granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) are effective at present. On the other hand, erythropoietin is used as a therapeutic agent for erythropenia. The employment of interleukin-6, interleukin-11, thrombopoietin and the like as medicines is in progress for treating thrombopenia. In addition, the employment of granulocyte-macrophage colony-stimulating factor (GM-CSF) and the like as therapeutic agents for myelosuppression is in progress.
For example, compounds formed by the substitution of a sugar by a N-acyl-N-alkylamino group at the 1-position are known (JP-B-1-40036) as compounds having defensive effect on infectious diseases caused by bacteria, fungi, etc.
On the other hand, dipeptidyl peptidase IV is a serine protease that detaches the N-terminal dipeptide of a protein or peptide in which the second amino acid residue from the N-terminus is proline or alanine. In mammals, dipeptidyl peptidase IV is present in various organs such as liver, kidney, small intestine, hemocytes, etc. Although the biological role of dipeptidyl peptidase IV has not completely been established, it is considered that dipeptidyl peptidase IV participates in the metabolism of neuropeptides and hormones, the activation of T cells, the intrusion of HIV into lymph cells, and the like (see Immunol. Today, Vol. 15, 180-184 (1994) and J. Clin. Invest., Vol. 78, 906-913 (1994)). Therefore, dipeptidyl peptidase IV inhibitors are expected to be usable as hormone modulators, immunomodurators, anti-inflammatories, antiallergics, antirheumatics, anti-HIV agents, etc. In addition, it has recently been proved that glucagon-like peptide 1, which is an stimulating factor for insulin secretion in spleen, is inactivated by dipeptidyl peptidase IV. Therefore, the dipeptidyl peptidase IV inhibitors are promising also as therapeutic agents for type II diabetes (see Diabetes, VOl. 47, p. 1253 (1998)).
As a compound having both effect on hemocytes such as leukocytes and inhibitory effect on dipeptidyl peptidase IV, Val-boroPro is known which is a dipeptide containing boron (see International Publication No. 94/03055). However, it has been reported that such compounds having boron in the molecule are decreased in activity in a neutral buffer solution because an amine coordinates with the boron, an active center (see J. Am. Chem. Soc., Vol. 116, p. 10860 (1994)), and that they exhibit an insufficient preference for dipeptidyl peptidase IV over other enzymes (see J. Med. Chem., Vol. 39, p. 2087 (1996)). It is not easy to develop these compounds as medicines, and they are utterly different in skeleton from the compounds of the present invention. As compounds similar in skeleton to the compounds of the present invention, there are known sulphostin and compounds analogous thereto which have inhibitory effect on dipeptidyl peptidase IV (see International Publication No. 99/25719 and JP-A-2000-327689).